Tertiary-aminoalkyl 4-alkylamino-2-hydroxybenzoates, their salts and preparation thereof



United States Patent TERTIARY-AMINOALKYL 4-ALKYLAMINO-2- HYDROXYBENZOATES, THEIR SALTS AND PREPARATION THEREOF Raymond 0. Clinton, North Greenbush, and Stanley C. Laskowski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application October 9, 1953, Serial No. 385,282

24 Claims. (Cl. 260294.3)

This application relates to tertiary-aminoalkyl esters of 4-alkylamino-2-hydroxybenzoic acid, and to water-soluble acid-addition salts thereof, and to the preperation of these new compounds.

We have found that the basic esters of the general formula NHR C|OOXNRR' where R" is a lower alkyl radical, X is a lower alkylene radical and NRR' is a lower aliphatic-like tertiary-amino radical, exhibit valuable pharmacological properties. These esters, preferably in their form of water-soluble acid-addition salts, have been found to possess outstanding local anesthetic activity. These esters are also useful to produce deep, long-lasting anesthesia in dental surgery when used in combination with other basic esters such as the tertiary-aminoalkyl 4 amino 2 hydroxybenzoates which are disclosed and claimed in our copending appli cation, Serial Number 385,281, filed October 9 1953.

This application is a continuation-in-part of our appli cation Serial Number 168,842, filed June 17, 1950, now abandoned. Since the filing of our parent application W. Keil et a1. [Arzneimittel-Forsch. l, 218 and 326 (1951)] and Grimme and Schmitz [Ber. 84, 734 (1951)] have also described the compounds disclosed and claimed in our said parent and present applications.

In the above general formula, the lower alkyl radical designated as R" preferably has from 1-6 carbon atoms, including methyl, ethyl, n-propyl, n-butyl, isobutyl, 2- amyl, n-hexyl, and the like. The lower alkylene radical represented by X has preferably 2-4 carbon atoms, and has its two free valence bonds on difierent carbon atoms. Thus X includes such examples as CH2CH2,

CH2J3H(CH:) CH2CH2CH2CH2*, CH2CH(CH3)CH2, and the like. The lower aliphatic-like tertiary-amino radical shown above as NRR' comprehends lower dialkylamino radicals where R and R are lower alkyl groups, alike or difiere'nt, and each alkyl group having preferably 1-6 carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diiso'propylamino, di-n-butylamino, di-n-hexylamino and the like. Further, the lower aliphatic-like tertiary-amino radical designated as NRR' encompasses those radicals where R and R are joined directly or through an oxygen atom to form saturated N-heteromonocyclic radicals having -6 ring atoms, illustrated by examples such as l-piperidyl, 2-methyl-1-piperidyl, 3 ethyl 1 piperidyl, 4-methyl-1- piperidyl, 2,6-dimethyl-l-piperidyl, l-pyrrolidyl, Z-methyll-p'yrrolidyl, 2,5 dimethyl-I-pyrrolidyl, 4-morpholinyl, and the like.

The above basic esters are prepared by esterifying 4- nitro-Z-hydroxybenzoic acid to produce the tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate having the formula where X and NRR' have the meanings given hereinabove, and reducing said basic 4-nitro-2-hydroxybenzoate to the corresponding tertiary aminoalkyl 4-amino-2-hydroxybenzoate and then alkylating said 4-arnino ester to form the related tertiary-aminoalkyl 4-alkylamino-2-hydroxybenzoate. A specific illustration of this procedure is the formation of Z-dimethylaminoethyl 4-n-butylamino-2- hydroxybenzoate by esterifying 4-nitro-2-hydroxybenzoic acid to produce Z-dimethylaminoethyl 4-nitro-2-hydroxybenzoate and reducing the latter to form Z-dimethylaminoethyl 4-amino-2-hydroxybenzoate and alkylating said 4 amino ester to produce Z-dimethylaminoethyl 4-n-butylamino-Z-hydroxybenzoate. We carried out the esterification of 4-nitro-2-hydroxybe'nzoic acid to produce the corresponding tertiary-aminoalkyl ester in various ways. In one procedure, the 4-nitro-2-hydroxybenzoic acid was reacted with a tertiary-aminoalkyl halide. In another procedure, a lower alkyl 4-nit-ro-2-hydroxybenzoate was transesterified with a tertiary-aminoalkanol. in still another procedure, the 4-nitro-2 hydroxybenzoic acid was first treated with a haloalkanol to produce a haloalkyl ester which was reacted with a secondary amine to yield the desired tertiary-aminoalkyl ester. Thus, in the above speciiic illustration, Z-dimethylarninoethyl 4-nitro-2-hydroxybenzoate is prepared by reacting 4-nitro-2-hydroxybenzoic acid with Z-dimethylaminoethyl chloride; by reacting methyl 4-nitro-2-hydroxybenzoate with Z-dimethylamihoethanol; or by first reacting 4-nitro-2-hydroxybenzoic acid with ethylene chlorohydrin and treating the resulting 2- chloroethyl 4 nitro Z-hydroXybenzoate with dimethyl amine.

The reduction of the tertiary-aminoalkyl 4-nitro-2- hydrox'ybenzoates to the corresponding 4-amino-2-hydroxybe'nzoates was carried out both by chemical meth' ods and by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. Catalysts suitable when catalytic hydrogenation is used include Raney nickel, platinum, palladium, or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

The alkylation of the basic 4-amino esters to produce the related tertiary-aminoalkyl 4-alkyamino-2-hydroxybenzoates was preferably carried out by reductively alkylating with an alkanol. An illustration is the formation of 3-(Z-methyl-l-pyrrolidyl)propyl 4 n-propylamino-2- hydroxybenzoate by treating a mixture of the corresponding basic 4-amino-Z-hydrdxybefizoate and propionaldehyde with chemical reducing agents, such as zinc dust and acetic acid, iron and acetic acid, or with hydrogen under pressure using catalysts such as platinum, palladium, Raney nickel, or other catalysts generally effective in reductive alkylations using aliphatic aldehydes.

Our tertiary-aminoalkyl 4-alkylamino-2-hydroxybenzoates are therapeutically active whether employed as the free bases or as their salts with relatively non-toxic organic or inorganic acids. We found it convenient to isolate the basic esters as their hydrochlorides. However, other acid-addition salts are within the scope of our invention. Such additional salts include the hydrobromides,

sulfates, phosphates, citrates, sulfamates, tartrates, suc-.

(1) Tertiary-aminoalkyl 4-nitro-Z-hydroxybenzoates These basic esters were prepared from 4-nitro-2-hydroxybenzoic acid by the following esterification variants: by the reaction of 4-nitro-2-hydroxybenzoic acid with a tertiary aminoalkyl halide; by the reaction of a lower alkyl 4-nitro-2-hydroxybenzoate with a tertiary-aminoalkanol; or by the reaction of 4-nitro-2-hydroxybenzoic acid with a haloalkanol followed by treatment of the resulting haloalkyl ester with a secondary amine.

The first variant is illustrated by the following preparation of Z-diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride: To a stirred, refluxing solution of 137.5 g. of 4-nitro-2-hydroxybenzoic acid in 800 ml. of isopropanol was added dropwise 110 g. of 2-diethylaminoethyl chloride during the course of one and one-half hours. The resulting heterogeneous mixture was stirred and refluxed for an additional seven hours, cooled, and the dense white precipitate was collected. The filtrate was evaporated to dryness in vacuo and the resulting residue was triturated with acetone. The acetone-insoluble material was combined with the original precipitate and the material was recrystallized several times from ethanol in the presence of a small amount of anhydrous hydrogen chloride. There was obtained 161.4 g. (67.7%) of 2- diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride, M. P. 179.6180.4 C. (corn), crystallizing in white needles.

The second variant of reacting a lower alkyl 4-nitro-2- hydroxybenzoate with a tertiary-aminoalkanol is illustrated by the following preparation of 3-(2-rnethyl-lpiperidyl)propyl 4-nitro-2-hydroxybenzoate hydrochloride: A mixture of 84.5 g. of ethyl 2-hydroxy-4-nitrobenzoate, 70.8 g. of 3-(Z-methyl-l-piperidyl)propanol, 700 ml. of dry toluene and 200 mg. of sodium methoxide was slowly distilled through an eflicient fractionating column. The evolution of ethanol was slow, requiring forty-eight hours for completion. The residue was evaporated in vacuo and the resulting viscous oil was dissolved in ethyl acetate and treated with an excess of ethereal hydrogen chloride. The resulting thick heavy oil was separated by decantation and dissolved in dry acetone.-

On scratching and cooling this solution a dense white precipitate appeared. Several recrystallizations from isopropanol gave 55.7 g. (39%) of 3-(2-methyl-l-piperidyl)- propyl 4-nitro-2-hydroxybenzoate hydrochloride, crystallizing in needles, M. P. l73.0-173.8 C. (corn).

The third variant for preparing the tertiary-aminoalkyl 4-nitro-2-hydroxybenzoates is illustrated as follows: A mixture of one mole of 4-nitro-2-hydroxybenzoic acid and three moles of ethylene chlorohydrin was heated to reflux and dry hydrogen chloride was passed into the reaction mixture for eight hours. The excess ethylene chlorohydrin was removed by distilling in vacuo and the residue when crystallized from absolute ethanol yielded 2-chloroethyl 4-nitro-2-hydroxybenzoate, M. P. 87.488.4 C. (corn). The corresponding 2-bromoethyl ester, M. P. 74.7-74.9" C. (corr.), resulted when ethylene bromohydrin was used in place of ethylene chlorohydrin. A mixture of one mole of 2-chloroethyl (or Z-bromoethyl) 4- nitro-2-hydroxybenzoate and two moles of diethylamine and 1500 ml. of toluene was refluxed for twenty-four hours. After removal of the solvent by distilling in vacuo, the residue was dissolved in hydrochloric acid, the acidic solution was treated with decolorizing charcoal and filtered. The filtrate was made alkaline with potassium carbonate and the mixture was extracted with ethyl acetate. After removal of the ethyl acetate by distilling in vacuo, the residue was dissolved in absolute ethanol and the alcoholic solution was treated with excess hydrogen chloride in ether. Addition of excess ether precipitated the 'basic ester salt, 2- diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride, which was recrystallized from isopropanol.

Other tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate hydrochlorides prepared according to the foregoing procedures include those given in Table A.

Additional tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate hydrochlorides which can be prepared accordingto the above procedures include the following: 4-dimethylaminobutyl 4-nitro-2-hydroxybenzoate hydrochloride; 3- dimethylamino-Z-propyl 4-nitro-2-hydroxybeuzoate hydrochloride; 2-di-n-butylaminoethyl 4-nitro-2-hydroxy benzoate hydrochloride; Z-di-n-hexylaminoethyl 4-nitro- Z-hydroxybenzoate hydrochloride; 4-(1-piperidyl)-butyl 4-nitro-2-hydroxybenzoate hydrochloride; 2-(l-pyrrolidyl)ethyl 4-nitro-2-hydroxybenzoate hydrochloride; 3-(2- methyl-l-pyrrolidyl)propyl 4-nitro 2 hydroxybenzoate hydrochloride; and 2-(2,5-dimethyl-1-pyrrolidyl)-ethyl 4- nitro-2-hydroxybenzoate hydrochloride.

The corresponding free bases of the foregoing salts,;.

i. e., the tertiary-aminoalkyl 4-nitro-2-hydroxybenzoates, are highly-colored, high melting solids soluble in polar solvents such as water, methanol, ethanol, etc. and insoluble in non-polar solvents. They probably have the structure of inner salts, with the formula (2) Tertiary-aminoalkyl 4-amino-2-hydroxybenzoazes- These esters are prepared by reducing the hereinabove described tertiary-aminoalkyl 4-nitro-2-hydroxybenzoates.

This reduction is carried out either by chemical means or by catalytic hydrogenation methods.

Exemplary of the chemical method is the following preparation of 2-(2,6-dimethyl-1-piperidyl)ethyl 4-amino- 2-hydroxybenzoaterTo a stirred boiling mixture; of g;

of iron powder, 200 ml. of Water, 300 ml. of ethanol and 1 ml. of concentrated hydrochloric acid was gradually added in portions 80.7 g. of 2-(2,6-dimethyl-l-piperidyl)- ethyl 2-hydroxy-4-nitrobenzoate hydrochloride. Each addition produced an exothermic reaction. When the addition had been completed, the mixture was stirred at the boiling point for twenty minutes. While continuing stirring and heating, 30 to 40 g. of solid bicarbonate was cautiously added, and the resulting mixture was stirred and heated an additional ten minutes. The mixture was filtered hot and the filter cake washed well withhot ethanol.-

TABLE B The combined filtrates were concentrated invacuo until 5 all ethanol was removed. The residual aqueous suspen sion of the crystalline base was cooled and filtered, and the precipitate was washed well with cold water. The I v precipitate crystallized from n-heptane in rosettes of beau C OO (CHZ) NRR tiful long slender needles of 2-(2,6-dimethyl-l-piperidyl)- ethyl 4-amino-2-hydroxybenzoate, M. P; 1ll.0lll.6 C. M. P./ 0. (corn) (corn). The phosphate of this basic ester was prepared 12 NRR from mole equivalents of base and phosphoric acid Base Phosphate (HaPO4) in absolute ethanol and recrystallized by dissolving in a minimum amount of hot water, filtering and 2, N( Hs) lam-137.2 219.7-220.0= slowly diluting with hot absolute ethanol. The resulting g 133 gg jg gf salt, 2 (2,6 dlmethyl 1 plperldyl)ethyl 4 ammo-Z- NCiH 69.0-62.0 2035-2049 hydroxybenzoate phosphate, melts at 197.7-2000" C. 3 5821213321 1: (corn). g biCiHn oil h g0l .020 .5 A specific illustration of the catalytic hydrogenation 5 8fi8d iii 4 ig iigiig method of preparing our tertlary-amln'oa'lkyl 4-ammo-2- 3 M02115): oil 2123 hydroxybenzoates is the following synthesis of 3-(1-p'iperidyl)propyl 4-amino-2-hydroxybenzoate: A mixture of NC 10.0 g. of 3-(l-piperidyl)propyl 4-nitr0-Z-hyclroxylienzo NCulHn=2-Ir1ethyl-l-piperidyl. ate hydrochloride, 500 mg. of platinum oxide and 150 ml. ggfgf fgggfilf 15 CHNHQCHZMCHW of 50% aqueous ethanol was hydrogenated in a Parr gg rso=t m r holin l. Burgess hydrogenato'r at 25-45 C. and 20-'-50 lbs. pres-- mf ggfg fiiggg at (cowl sure. The theoretical amount of hydrogen was absorbed ion ygi oe lo ide. in fifteen to twenty minutes The mixture was filtered crystalllzed from dilute ethanol as the monohydrate, M. P.8790 C. and evaporated to dryness in vac'uo. The residual white Additiollfll ter iary-aminoalkyI 4-amino-2-hydroxybensolid was crystallized from ethanol to give a high yield mates w h can be P p accordmg to the a v of 3-(l-piperidyl)propyl 4-amino-2-hydroxybenzoate hyprocedures include the following: 4-dimethylaminobutyl drochloride, M. P. 2395-2402 c; (.c'orr.). The phOS r -2- y y y phate salt of this basic ester was prepared as follows: f Y Xy Y Y 3-(l-piperidyl)propyl 4-amino-2-hydroxybe'nzoate h dro: amwolhydroxybenwate; rp p yb y chloride was converted to the crystalline base by treatz-hydfoxybeliloate; -PY 3 Y- ment of an aqueous solution thereof with an excess of d y y -p l bp pyl a sodium carbonate solution. The resulting base when hyd y o d y -p y treated with a one mole proportion of 85% phosphoric y Q- Y fP Y acid in absolute alcohol solution readily yielded 3-(1- The foregoing tertlary-amlnoalkyl 4-am1no-2-hydroxypiperidyl)propyl 4-amino-2-hydroxybenzoate phosphate, benzoates are als convenlently prepared from 4-nitro-2- forming rosettes of large blunt needles from 95% ethanol, hYdTQXYbeIiZOICIaQd Its lower alkyl esters through the M. P. 204.7205.0 C. (dec.) (com); Z-benzyloxy derivatives according to the steps illustrated Other tertiary-aminoalkyl 4-amino-2-hydroxybenzoates in the lQW g qu where is a lower alkYi prepared according to the above procedures include those group and X and NRR' have the meanings given hereingiven in Table B. above:

on oolnolne (00K COOCHzCaHr \\II \a N O:

OCHgCuH; NO: NO: 7 l

I I IV 00011 0H oornolnl o i111 0012" COOR lfn, I m, Not

V IV

on oomolm oonlclrn COO X-NRR Thus, 4nitro-2-benzyloxybenzoic acid (H) is prepared either by benzylating 4-nitro-2-hydroxybenzoic acid (step I) to form benzyl 4-nitro-2-benzyloxybenzoate (A), which is saponified in step II to yield'the desired 4-nitro- 2-benzyloxybenzoic acid or by benzylating a lower alkyl 4-nitro-2-hydroxybenzoate (step I) to form a lower alkyl 4-nitro-2-benzyloxybenzoate (A), which in step 11 is saponified to the desired acid (B). 4-nitro-2-benzyloxybenzoic acid is then esterified in step III to produce the corresponding tertiary-aminoalkyl 4-nitro-2-benzyloxybenzoate (C) which in step IV is reduced to the corresponding tertiary-aminoalkyl 4-amino-2-benzyloxybenzoate (D). Then, in step V, the tertiary-aminoalkyl 4- amino-2-hydroxybenzoate (E) is produced by catalytically debenzylating the basic 4-amino-2-benzyloxybenzoate (D). Steps IV and V can be carried out in the same reaction vessel without isolating compound D when the reduction is carried out catalytically, e. g. as with palladium on charcoal. As a specific illustration of steps III, IV and V, 4-nitro-2-benzyloxybenzoic acid is esterified to produce the 3-(2-methyl-1-piperidyl)propyl 4-nitro-2'benzyloxybenzoate which is then reduced to the corresponding 3- (Z-methyl-1-piperidyl)propyl 4-amino-2-benzyloxybenzoate, which, in turn, is reduced to 3-(2-methyl-l-pipe1idyl)- propyl 4-amino-2-hydroxybenzoate.

We carried out esterification step III by two variants:

in one, the 4-nitro-2-benzyloxybenzoic acid was reacted with a tertiary-aminoalkyl halide; and in the other, said acid was first converted into the corresponding acid chloride which was then treated with a tertiary-aminoalkanol. The reduction step IV was carried out both by chemical methods and by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate, tin and hydrochloric acid, etc. We found iron and hydrochloric acid was to be preferred. Catalysts suitable when catalytic hydrogenation was employed include Raney nickel, platinum, palladium, etc. Reduction step V was carried out by catalytic hydrogenation, e. g. using preferably palladium, although platinum and Raney nickel can be used, the latter at higher temperatures and pressures.

The tertiary-aminoalkyl- 4-amino-2-benzyloxybenzoates (D) and the process (step V) of converting them into the corresponding 4-amino-2-hydrozybenzoates are disclosed and claimed in our copending application Serial Number 242,421, filed August 17, 1951, now Patent No. 2,662,888.

The foregoing tertiary-aminoalkyl 4-amino-2-hydroxybenzoates and their preparation are described and claimed in our co-pending application, Serial Number 385,281, filed October 9, 1953.

(3) Tertiary-aminoalkyl 4-alkylamin0-2- hydroxybenzoates These basic esters were prepared by alkylating theabove-described tertiary-aminoalkyl 4-amino-2-hydroxybenzoates. Exemplary of such a procedure is the following reductive alkylation using catalytic hydrogenation to produce 3-(1-piperidyl)propyl 4-n-butylamino-2-hydroxybenzoate: Ten grams of 3-( l-piperidyl)propyl 4-nitro-2- hydroxybenzoate was reduced as described hereinabove under section (2). The catalyst was removed by filtration and to the filtrate was added 4.5 m1. of n-butyraldehyde and 500 mg. of platinum oxide. The mixture was again reduced in a Parr-Burgess hydrogenator at 50 lbs.

and 45 C. The theoretical amount of hydrogen was ab- 8 benzoate dihydrochloride monohydrate, white cottony needles from isopropanol-acetone, M. P. 1l5.8'118.6 C. (corn).

Alternatively, the reductive alkylation of the tertiaryarninoalkyl 4-amino-2-hydroxybenzoates was carried out using chemical reducing agents, as illustrated by the following preparation of 3-(2-methyl-1-piperidyl)propyl 4- n-butylamino-2-hydroxybenzoate: To a stirred refluxing mixture of 24.8 g. of 3-(2-methyl-1-piperidy1)propyl 4-amino-2-hydroxybenzoate, 22.2 g. of zinc dust, 20.9 g. of glacial acetic acid and 200 ml. of benzene was added dropwise over a period of twenty minutes a solution of 8.9 g. of n-butyraldehyde in 200 ml. of benzene. When the addition was complete, the mixture was stirred and refluxed for an additional one hour period, filtered while hot, and the insoluble filter cake was washed thoroughly with dilute acetic acid and benzene. The combined filtrates were carefully adjusted to litmus-basicity with sodium hydroxide solution, mixed well, and the benzene layer was separated. After drying, the benzene extract was evaporated in vacuo. The residual golden-yellow viscous oil obtained (27.0 g.) was dissolved in dilute hydrochloric acid, the solution was'washed with ether, decolorized with'activated carbon, and made basic-with solid potassium carbonate. The liberated base was extracted into ethyl acetate, the solution was dried and decolorized with-activated carbon, and the ethyl acetate was removed in vacuo. The residue was dissolved in ether, again decolorized with activated carbon, and the ether was removed in vacuo, finally at C. and 0.01 mm. for three hours. After filtration through a layer of a filter aid on a sintered glass funnel, the analytically pure 3-(2-methyll-piperidyDpropyl 4-butylamnio-2-hydroxybenzoate (19.2 g.) was obtained as a nearly colorless, very viscous'oil.

Other tertiary-aminoalkyl 4 alkylamino 2 hydroxybenzoates prepared according to the above procedures include those given in Table C. Since most of these esters are oils, the melting points of their flavianate salts are given. Melting points of the solid basic esters and their hydrochloride acid-addition salts .where prepared, are given in the footnotes. All melting points given in Table C are corrected.

TABLE 0 NIIRII n I Flavianate R NRR M. P., a o.

n-Cz 1 2 N6 ma t-193.2 n-C Hg 2 N (CH3): 174. 0-177. 8 n-O|Hu 2 M 111); 183. 1-184. 0 11-0411! 2 N GzHs): 186. O-187. 5 l Ill-C 110 2 sHm 214. 7-215. 0 Inc-4H9 2 N CsHu 135. 5-136. 8 n-C H9 2 NC7 n 168. 11-170. 0 h 11-O4H. 2 NC4H3O d 226. 6-228. 4 c n 04H; N (CH3): 179. 7480. 8 hi 11-04119 3 N(GH3): 15S. 5-159. 4 k 11-04110 3 N(C:H5)2 147. 6-149. 3 II-CsHu 3 0513110 184. 2-185. 6 n-C Ha 3 NC Hu 176. 0-178. 0 n-CsHn 3 NCsHm 157. O-159. 2 11-04119 3 NC4HBO d 194. 8197. 0

I NCsHw=l-piperidyl.

b NCtHn=2-methy1'1-piperldyl.

: gith tdecorcipogitlon.

icra a me te at l43.5-145.5 O. and ih mzgllhmg; Cm d d ydrochloride melted at l y be ori emelted at 171.7 C. with d h Basic ester melted at 62.864.0 C. ecomposmon) prLggtiary-amino is -CH(CH )CHzN(CHa)2 or 3-dirnethylamino-2- 5 Diiiavianate.

Basic ester melted at 67.5-68.4 O.

l Dlhydrochloride monohydrate melted at 117.0--120.2 C.

The fiavianate salts were prepared by treatingethanolic solutions of the basic esters with an excess of fiavianic acid solution in absolute ethanol). The orange to orange-red colored crystalline salts were recrystallized from dilute ethanol or from glacial acetic acid.

Additional tertiary aminoalltyl 4 alkylamino-Z-hydroxybenzoates of our invention which can be prepared according to the above procedure include the following: 4-dimethylamin0butyl 4-methylamino 2 hydroxybenzoate; Z-di-n-butylaminoethyl 4-n-propylamino-2-hydroxybenzoate; Z-di-n-hexylaminoethyl 4-n-butylamino- Z-hydroxybenzoate; 4-(l-piperidyl)butyl 4-n-butylamino- Z-hydroxybenzoate; Z-(I-pyrrolidylkthyl 4-ethylar'nino Z-hydroxybenzoate; 3 (2 methyl-1-pyrrolidyl=)propyl 4-n-hexylamino-Z-hydroxybenzoate; and 2(.2,5 dim'ethyl-' 1--pyrrolidyl)ethyl 4-n-amylaminoQ-hydroxybenzoate;

The foregoing tertiary-amin'oalkyl 4-alkylarnino-'2- hydroxybenzoates were also conveniently prepared by cata'lytically hydrogenating the corresponding tertiaryami-noalkyl 4-alkylaminoQ-benzyloxybenzotiteS, thereby removing the benzyl group. The intermediate tertiaryaminoalkyl 4-alkylamino-2-benzyloxybenzoates were conveniently prepared by reductively alkylating with an alkanal the corresponding tertiary-aminoalkyl 4-amino-2- benzyloxybenzoates, which were described hereinabove under section (5). Such a preparation is exemplified by treating a mixture of 2-(2,5-dimethyl-l-pyrrolidyl)ethyl 4-amino-2-benzyloxybenzoate and n-butyraldehyde with chemical reducing agents, such as zinc dust and acetic acid, or with hydrogen under pressure in the presence of a hydrogenation catalyst such as platinum, palladium or Raney nickel.

Alternatively, the intermediate tertiary aminoalkyl 4-alkylamino-Z-benzyloxybenzoates were prepared by esterifying the corresponding 4-alkylamino-2-benzyloxybenzoic acids. This preparation and the preparation of the intermediate acids are illustrated by the following series of equations, wherein R isa lower alkyl group and X, NRR and R" have the meanings designated here- Thus, in step VI, a lower alkyl 4-nitro-2-benzyloxybenzoate (A') is reduced to r the corresponding 4-amino ester (P), which in step VII is alkylated to form the related 4-alkylamino ester (G). Saponification of this 4-alkylamino ester (G) in step VIII yields the parent acid (H) which when este'rified in step IX produces: the desired tertiary-aminoalkyl 4-alkylainind-2-benzyl6i(ybenzoate (I). The alkylation in step can be done reductively as described hereinabove using an alkanal or directly using an alkyl ester of an; inorganic acid, e. g., alkyl halide, alkyl sulfate, etc., in the presence of an acid acceptor generally suitable for such purpose, such as potassium carbonate or sodium carbonate. The esterification step IX can be carried out by different procedures such as: first converting the acid (H) to the acid chloride and treating the latter with a tertiary-aminoalkanol of the formula RRN-'-'-'X-OH; directly treating the acid (H) with a tertiary-aminoa'l'kyl halide of the formula RRNX-halogen. Alternatively, the basic ester (I) can be prepared as illustrated by step X, by an ester exchange reaction between the lower alkyl ester (G) and a tertiary-aminoalkanol of the formula RR'N-XOH.

The tertiary-aminoalkyl 4-alkylamino-Z-benzyloxybenzoates (J) and the process of converting them into the corresponding 4-alkylamino*Z-hYdroxybenzoates are disclosed and claimed in our copending application Serial Number 242,422, filed August 17, 1951, now Patent No. 2,662,889.

We claim: v V I. A member of the group consisting of a basic ester having the formula NHR nan-' OO X N (lower alkyl):

where R" is a lower alkyl radical and X is a lower alkylene radical having 24 carbon atoms.

3. An acid-addition salt of a basic ester having the formula dom-x-NRR' where R is a lower alkyl radical, X is a lower alkylene radical having 2-4 carbon atoms and NRR is a (lower alkylated)-1-piperidylradical.

4. An acid-addition salt of a basic ester having the formula where X is a lower alkyle'ne radical having 2-4 carbon atdms'.

11 5. An acidaddition salt of a basic ester having the formula (SOC-X-NRR where X is a lower alkylene radical having 2-4 carbon atoms and NRR is a (lower alkylated)-l-piperidyl radical.

6. An acid-addition salt of a basic ester having the formula NHR" COXNRR where R is a lower alkyl radical, X is a lower alkylene radical having 2-4 carbon atoms and NRR is a l-piperidyl radical.

7. An acid-addition salt of a basic ester having the formula IITH C Jig-n COO-X-NRR' where NRR is a tertiary-amino radical selected from the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated)-1-piperidyl, l-pyrrolidyl, (lower alkylated)-l-pyrrolidyl and 4-morpholinyl, R" is a lower alkyl radical and X is a lower alkylene radical having 2-4 carbon atoms, which comprises treatingin a reducing medium the corresponding tertiary-aminoalkyl 4-amino- Z-hydroxybenzoate with a lower alkanal.

14. A process of preparing a di(lower alkyl)aminoalkyl 4-alkylamino-Z-hydroxybenzoate having the formula 410 O-X-N (lower alkyl):

where R" is a lower alkyl radical and X is a lower a1- kylene radical having 2-4 carbon atoms, which comprises 12 treating in a reducing medium the corresponding di(lower alkyl)aminoalkyl 4-amino-2-hydroxybenzoate with a lower alkanal.

15. A process of preparing a tertiary-aminoalkyl 4- alkylamino-Z-hydroxybenzoate having the formula NHR tilHO-X-NRR where R" is a lower alkyl radical and X is a lower alkylene radical having 2-4 carbon atoms and NRR is a (lower 'alkylated)-1-piperidyl radical, which comprises treating in a reducing medium the corresponding tertiaryaminoalkyl 4-amino2-hydroxybenzoate with a lower alkanal.

16. A process of preparing a di(lower alkyl)aminoalkyl 4-n-butylamino-2-hydroxybenzoate having the formula O O OXN (lower alkylh where X is a lower alkylene radical having 2-4 carbon atoms, which comprises treating in a reducing medium the corresponding di(lower alkyl)aminoalkyl 4-amino-2- hydroxybenzoate with n-butyraldehyde.

17. A process of preparing a tertiary-aminoalkyl 4-nbutylamino-Z-hydroxybeuzoate having the formula OOO-XNRR where X is a lower alkylene radical having 2-4 carbon atoms and NRR is a (lower alkylated)-1-piperidyl radical, which comprises treating in a reducing medium the corresponding tertiary-aminoalkyl 4-amino-2-hydroxybenzoate with n-butyraldehyde.

18. A process of preparing a tertiary-aminoalkyl 4- alkylamino-2-hydroxybenzoate having the formula boo-ar-Nnn' where R" is a lower alkyl radical, X is a lower alkylene radical having 2-4 carbon atoms and NRR is a l-piperidyl radical, which comprises treating in a reducing medium the corresponding tertiary-aminoalkyl 4-amino-2- hydroxybenzoate with a lower alkanal.

19. A process of preparing a tertiary-aminoalkyl 4-nbutylamino-Z-hydroxybenzoate having the formula NH C (Hrll where X is a lower alkylene radical having 2-4 carbon atoms and NRR is a l-piperidyl radical, which comprises treating in a reducing medium the corresponding tertiary- 13 aminoalkyl 4-amino-2-hydroxybenzoate with n-butyraldehyde.

20. A process of preparing 2-diethy1aminoethyl 4-nbutylamino-2-hydroxybenzoate which comprises treating in a reducing medium 2-diethy1aminoethyl 4-amino-2-hydroxybenzoate with n-butyraldehyde.

21. A process of preparing 3-(l-piperidyl)propyl 4-nbutylamino-Z-hydroxybenzoate which comprises treating in a reducing medium 3-(1-piperidy1)propyl 4-amino-2- hydroxybenzoate with n-butyraldehyde.

22. A process of preparing Z-dimethylaminoethyl 4-nbutylamino-Z-hydroxybenzoate which comprises treating in a reducing medium Z-dimethylamiuoethyl 4-amino-2- hydroxybenzoate with n-butyraldehyde.

23. A process of preparing 3-(2-methyl1'piperidy1)- propyl 4-n-butylamino-2-hydroxybenzoate which comprises treating in a reducing medium 3-(2-methyl-1- piperidy1)propyl 4-amino-2-hydroxybenzoate with n-butyr aldehyde.

24. A process of preparing 2-(2-methyl-1-piperidyD- ethyl 4-n-butylamino-Z-hydroxybenzoate which comprises treating in a reducing medium 2-(2-methy1-i-piperidyl)- ethyl 4-amino-2-hydroxybenzoate with n-butyraldehyde.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Drain et aL: Jour. of Pharm. and Pharmacol. 1:784-87 1949). 

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC ESTER HAVING THE FORMULA
 6. AN ACID-ADDITION SALT OF A BASIC ESTER HAVING THE FORMULA
 13. A PROCESS OF PREPARING A TERTIARY-AMINOALKYL 4ALKYLAMINO-2-HYDROXYBENZOATE HAVING THE FORMULA 